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  • Title: An irregularity in the transmembrane domain helix correlates with the rate of insulin receptor internalization.
    Author: Li SC, Deber CM, Shoelson SE.
    Journal: Biochemistry; 1994 Nov 29; 33(47):14333-8. PubMed ID: 7947843.
    Abstract:
    Internalization of insulin and its receptor via receptor-mediated endocytosis is an important step in insulin-induced signal transduction. To investigate the structural determinants underlying the enhanced internalization rate observed for the insulin receptor transmembrane mutant Gly933-Pro934-->Ala-Ala (GP-->AA), we have designed and chemically synthesized two peptides, IR(TM)-GP and IR-(TM)-AA, corresponding respectively to the N-terminal portion of the wild-type and the mutant insulin receptor TM segment containing these sites. Conformational studies by circular dichroism (CD) spectroscopy on these two peptides in their monomeric states revealed that peptide IR(TM)-GP forms an irregular helix in the membrane-mimetic environments of sodium dodecyl sulfate (SDS) micelles with a possible "kink" in the helix imposed by its Gly-Pro sequence, while peptide IR(TM)-AA assumes largely classical alpha-helical structure under corresponding conditions. The helical pattern of peptide IR(TM)-AA was maintained at elevated temperatures, while the shape of the CD curve for peptide IR(TM)-GP was found to alter as a function of temperature. At higher concentrations, both peptides formed high molecular weight aggregates in SDS micelles, as demonstrated by SDS-PAGE gels, but peptide IR(TM)-AA was shown to aggregate more readily and more extensively than peptide IR(TM)-GP. Fluorescent dye-leakage experiments indicated that peptide IR(TM)-GP produces an enhanced disruption of the membrane bilayer in phosphatidylglycerol vesicles vs that induced by IR(TM)-AA.(ABSTRACT TRUNCATED AT 250 WORDS)
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